We recruited and screened 58 participants into NIAAA Screening protocol #14-AA-0181. We enrolled 61 participants into 5 protocols (14-AA-0144 (n=2), 15-AA-0186 (n=9), 17-AA-0114 (n=24), 17-AA-0152 (n=19) and 17-AA-0178 n=7). The circadian protocol #14-AA-0187 is on hold as we are prioritizing OUD studies (17-AA-0114). The radiotracer laboratory was finally completed in November 2018. 1. Effects of Drugs in Human Brain Elevated glutamate in thalamus in in alcohol use disorder (AUD): Association with thalamic diffusivity and with impulsivity. Led by Corinde Wiers AUD is associated with impulsivity, but mechanisms remain unexplored. We used proton magnetic resonance spectroscopy to investigate the correlation between glutamate levels in anterior cingulate cortex (ACC) and thalamus with impulsivity in n=15 patients with AUD and n=14 healthy controls (HC). We also assessed fractional anisotropy (FA) in thalamus and ACC with DWI. AUD had higher scores on the CAARS impulsivity scale (p=0.03), and higher glutamate levels in thalamus (t=2.2, p=0.04), but not in ACC (p=0.3) than HC. Glutamate levels in thalamus and ACC correlated positively with impulsivity (r=.58 p=0.03, and r=.55 p=0.036). FA was lower in AUD than HC in thalamus (t=2.1, p=0.04) but not in ACC (p=0.3). Within the AUD group only, glutamate levels and FA correlated negatively in thalamus (r=-.52, p=0.058) but not in ACC (r=-.43, p=.11). Our findings suggest that elevated glutamate l in thalamus contribute to impulsivity; and its association with reduced FA (marker of neuroinflammation) implicates neuroinflammatory processes. Brain Structural Changes in Cannabis Dependence: Association with Monoacylglycerol Lipase (MAGL). Led by Peter Manza There is limited understanding of biological processes that modulate adverse effects of cannabis in brain. To explore the role of the endogenous cannabinoid system (ECS) on the vulnerability to structural brain changes with chronic cannabis, we examined white matter integrity and gray matter cortical thickness (CT) differences between 89 individuals with cannabis dependence (CD) and 89 matched controls from the HCP. We tested whether cortical patterns for expression of ECS relevant genes (Allen Human Brain Atlas postmortem tissue) were associated with patterns of CT differences in CD. CD had lower FA than controls in white matter bundles innervating posterior cingulate and parietal cortex, basal ganglia, and temporal cortex. CD also had less CT in precuneus. Spatial patterns of CT in CD were associated with regional differences in MAGL, such that regions with higher MAGL (but not fatty acid amide hydrolase) had lower CT suggesting that regions with high MAGL expression may be more vulnerable to cannabis. 2. Dopamine (DA) and Addiction Striatal DA Increases During Naloxone Precipitated Withdrawal: Role of Kappa Receptors. Led by Ehsan Shokri The involvement of the DA system during opioid withdrawal has been underexplored. Here we used PET and 11Craclopride to measure DA changes in striatum induced by naloxone precipitated withdrawal (NPW) in 10 methadone maintained heroin users. Though NPW is associated with blockade of mu opioid receptors (MOR), we aimed to investigate the role of naloxone-induced kappa receptor (KOR) blockade. To address this, we studied whether patterns of striatal DA release during NPW were associated with striatal distributions of MOR, and KOR by analyzing PET images previously collected by other laboratories in 10 controls scanned with 11Ccarfentanyl for MOR and 10 controls scanned with 11C-LY2795050 for KOR. NPW increased striatal DA release most prominently in dorsal striatum (pFWE < 0.02). Increases in striatal DA were negatively associated with MOR (r = -0.6, p < 0.0001), and KOR (r = -0.8, p < 0.0001). The KOR distribution in striatum fully mediated the association between DA increases and MOR (p < 0.0001) and independently accounted for 45% of variance in DA increases. These findings implicate KOR in mediating the striatal DA increases during NPW in heroin abusers that might reflect blockade of KOR induced inhibition of DA release. 3. Methodological Studies- Connectome-based predictive and reproducible modelling of head motion: association with cognitive prediction. Led by Dardo Tomasi Head motion (HM) can confound functional connectivity measures, yet little is known about its neurobiological origin and its influence on brain-behavior prediction studies. Here we aim to develop a robust neuromarker of HM and to demonstrate its effect on brain-behavior predictions using twofold cross-validation. We uncovered a distributed network whose strength during a set of 8 different fMRI sessions (2 rest and 6 task) forecasted individual differences in HM and generalized to a novel group of individuals. The models that predicted 22 additional behavioral measures obtained outside the scanner using leave-one-out cross-validation partially overlapped with brain areas that predicted HM. However, only language comprehension and fluid intelligence, which were measures that uniquely showed association with HM, reproduced the predictions in a novel group. Findings suggest that HM reflects necessary functional connectivity for exerting inhibitory motor control and highlight the importance of replicating brain-behavior prediction association studies in an independent sample of subjects. Eye-Blink driven changes in functional connectivity during rest and task conditions. Led by Sukru Demiral. Eye-blink (EB) rates are believed to reflect in part the state of arousal. Though fMRI studies have assessed BOLD signals related to EB, the temporal relationship with the ascending arousal network (AAN) is not known. Here we explored regional brain dynamics associated with spontaneous EB during reward task and resting state fMRI in 16 healthy subjects using a 3T scanner and an Applied Science Laboratories eye tracker to measure EB. We constructed detrended z-scores of IRF-convolved values of EB, which were used to correlate with voxel-wise brain activity with lags from -3 to +3 TRs, and with preselected ROI from AN. We showed EB synchrony in ROIs from AAN during the task, but not during rest, that peaked earlier in periacqueductal gray, peduculopontine and dorsal raphe than in locus coeruleus and parabrachial complex. Voxel analyses additionally revealed EB synchrony in thalamic and visual regions followed by synchronous peak activity in cerebellum, caudate and putamen., which are areas associated with visual and emotional arousal systems.